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3109 Background: Poly(ADP-ribose) glycohydrolase (PARG) is an enzyme that catalyzes the removal of poly-ADP-ribose (PAR) chains from proteins during DNA damage repair. PARG inhibition leads to selective cell death in tumors with underlying replication fork defects, including BRCAm tumors, through a mechanism distinct from PARP inhibition. ETX-19477 is an oral, potent, and selective PARG inhibitor that shows robust preclinical activity in mouse models of ovarian, breast, and gastric cancers. Methods: ERADIC8 is an open-label, multicenter, Phase 1/2 study, consisting of two parts, dose escalation and dose expansion. A Bayesian Optimal Interval Design was used to enroll patients (pts) into dose escalation cohorts, with enrichment for pts with BRCAm high grade serous ovarian (HGSOC) and breast cancers. The primary objective is to assess safety/tolerability of ETX-19477 and define the maximum tolerated dose (MTD) and recommended Phase 2 dose(s). Secondary and exploratory objectives include pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity per RECIST v1.1. ETX-19477 is given orally once or twice daily in 21-day cycles. Results: As of Jan 6 2026, 45 pts were enrolled into the study across 11 dose levels (range: 80-750 mg QD, 190-350 mg BID). Tumor types included ovarian (n=24, BRCAm: 18), breast (n=8, BRCAm: 7), endometrial (n=6, BRCAm: 0), colorectal (CRC, n=3, BRCAm: 1), and other (n=4, BRCAm: 0) cancers. Treatment-related AEs (TRAEs; any grade) occurring in >20% of pts were nausea (53%), vomiting (38%), and fatigue (24%). The only Gr3 TRAE occurring in >5% of pts was neutropenia (16%). There was one Gr4 TRAE of neutropenia in 1 pt (2%) and no Gr5 TRAEs. ETX-19477 exposure is dose proportional, and the BID regimen achieves >85% PARG inhibition throughout the dosing interval in a blood-based PAR accumulation pharmacodynamic assay. As of the data cutoff, dose escalation is ongoing at 350 mg BID (MTD has not been defined) and dose expansion is ongoing at 200-300 mg BID. Among BRCAm, HGSOC pts enrolled at BID dose levels, there were 7 evaluable pts with a median of 4 prior lines of therapy (range 2–11): 2 pts achieved a partial response (PR, 29%) and 3 pts achieved stable disease (SD, 43%). Both pts with PRs were platinum-resistant and received prior PARP inhibitor treatment. 1 pt with BRCAm CRC remains on active therapy (250 mg BID) with SD for 7 months. Conclusions: ETX-19477 was well tolerated and showed anti-tumor activity in heavily pretreated pts with BRCAm, platinum-resistant HGSOC during dose escalation. These findings provide the first clinical proof-of-concept of PARG inhibition in HGSOC. ETX-19477 is being further evaluated in the dose expansion phase of the study. Clinical trial information: NCT06395519 .

3118 Background: Improved risk stratification is critically needed across multiple cancers to guide treatment decisions. This includes reducing overtreatment in Ductal Carcinoma in Situ (DCIS), addressing late recurrence risk in estrogen receptor-positive/lymph node-negative (ER+/LN-) breast cancer (BC), and refining prognosis in head & neck squamous cell carcinomas (HNSCC), and high-grade serous ovarian carcinoma (HGSOC). Tumor-infiltrating lymphocytes (TILs) reflect anti-tumor immunity, whereas tumor-associated macrophages (TAMs) polarize toward anti-tumor M1-like (CD68+) or immunosuppressive M2-like (CD163+) phenotypes. Integrating TILs with TAM polarization markers may better capture inflammatory balance and improve outcome prediction. We developed a hematoxylin and eosin (H&E)-only AI method (VAIP) to quantify TILs and virtual CD68/CD163 TAMs to develop multi-cancer based potential prognostic models. Methods: TILs were detected on H&E with HoVer-UNet, and virtual CD68 and CD163 macrophages were inferred with VISTA. In cancer regions, we computed cell densities and immune-balance ratios and trained cancer-specific Cox models with compact feature sets (DCIS 6; HGSOC 7; ER+ 4; HNSCC 4). Prognostic stratification used disease-free survival (DFS) for DCIS (N=273), HGSOC (training N=165, independent test N=220), and ER+ BC (training N=144, test N=622), and overall survival (OS) for HNSCC (N=77), reflecting clinical endpoints. Evaluation used cross-validation for cohorts without an external test set (DCIS, HNSCC) and independent training and testing when independent cohort was available (HGSOC, ER+). Results: Risk stratification performance across cancer types is in Table 1. The DCIS model used 6 features, largely TIL-macrophage contrast ratios (TIL/M2, TIL/M1). HGSOC used 7 features with a similar ratio-heavy immune-balance signature, plus macrophage-normalized density and polarization metrics (e.g., M1/N, M/N). In contrast, ER+ BC and HNSCC achieved best performance with 4 features dominated by macrophage measures, particularly M2 density and the M1/M2 ratio. Across sites, CD163-related macrophage metrics and immune-balance ratios were consistently informative. Conclusions: Integrating H&E-visible TILs with virtual CD68/CD163 TAMs enables fully automated, H&E-only prognostic biomarkers that stratify OS and DFS across multiple cancers, demonstrating consistent prognostic value in DCIS, ER+ BC, HGSOC, and HNSCC. These findings support further study of this histomorphometric risk classifier through broader external and prospective validation. Performance across cancer types. Cancer Type Cohort C-index HR [95% CI] p-value DCIS All 0.616 1.76 [1.20-2.59] <0.001 DCIS RT/No-treatment 0.624 1.94 [1.15-3.26] 0.003 HGSOC Test 0.553 1.38 [1.02-1.87] 0.030 ER+ BC Test 0.577 1.51 [1.00-2.28] 0.004 HNSCC All 0.603 1.92 [1.03-3.36] 0.012

1633 Background: CAR-T cell therapy has transformed outcomes of hematologic malignancies and is poised to expand into solid malignancies. However, broader use of CAR-T remains constrained by the need for timely cytokine release syndrome (CRS) detection. Current episodic monitoring may miss early physiologic changes. Wearable digital health technologies (DHTs), offering continuous monitoring and real-time alerts, could enable earlier CRS detection, further support outpatient delivery, and expand access to CAR-T and potentially other immunotherapies associated with CRS. Methods: This single-center observational study (NCT05018208) enrolled patients receiving FDA-approved CAR-T products in the outpatient setting at Mayo Clinic, Rochester MN. Management of post-CAR-T complications (e.g. CRS) followed the institution’s standard of care. Patients were monitored from day -5 to day +30 post infusion with intermittent remote patient monitoring (SoC) and an arm-worn wearable device for continuous monitoring (DHT). Patients were included in this analysis if DHT data were available for ≥ 5h of data/day or ≥ 2h of data/night on ≥2 days or nights for baseline and ≥1 day or night within 72h prior to CRS, or at least 2h within 4h of CRS onset, or if DHT was available for ≥7 days/nights post infusion with no CRS event. CRS detection time by DHT was defined as the onset of pyrexia or threshold-based deviation from an individual’s baseline pulse distributions. Results: 32 patients were included in this report (median age 64 years, gender 12 F/20 M, diagnoses 18 MM/14 NHL). 25 patients experienced a CRS event, with maximum CRS grades ranging from 1-3 (16 G1, 8 G2, 1 G3). 24/25 patients with CRS required tocilizumab/steroid. Median CRS onset time was 3.4 days (range 0.4-18.4). 12/32 patients had sufficient DHT data (7 CRS, 5 no CRS) for analysis. 5 patients with CRS had a DHT detection time in advance of the SoC by a median of 13h (range 2.8 - 69.2). The DHT prediction of CRS by baseline HR change was earlier than the first episodic fever by a median of 14.5h (range 13-77.5). The remaining 2/7 patients who did not have CRS detected by the DHT had missing DHT data for more than 45h before a treated CRS event. DHT detected CRS in 2/5 patients without CRS according to SoC. One patient had fever caught with intermittent monitoring. The other was treated for neutropenia fever with suspicion of CRS and/or infection. Conclusions: These results offer evidence that continuous DHT can identify CRS events earlier than intermittent monitoring (SoC). Despite limitations related to compliance with wearable device use and data missingness, and variability in clinical management of CRS, we highlight the usability of DHT and its potential for future studies with optimized strategies to address these limitations. Clinical trial information: NCT05018208 .

12007 Background: YAs with cancer, defined as those diagnosed prior to the age of 40, may experience greater symptom burden compared to those diagnosed at older ages. We evaluated the impact of an ePROM-triggered, CC-based, supportive care intervention on symptom burden in YAs with cancer. Methods: The Enhanced, Electronic Health Record-facilitated Cancer Symptom Control (E2C2) trial was a cluster-randomized, pragmatic trial (NCT03892967) that enrolled oncology patients seen at Mayo Clinic Rochester and within the Mayo Clinic Health System (sites in Minnesota and Wisconsin) between March 2019 and January 2023. Patients routinely reported the severity of six SPPADE symptoms (Sleep deficit, Pain, Physical function impairment, Anxiety, Depression, and Energy deficit/fatigue) on 11-point numerical rating scales. Symptom severity was classified as none to mild (0-3), moderate (4-6), or severe (7-10). Those with moderate or severe symptoms were offered symptom management education, while those with severe symptoms were also offered the option to work virtually with a symptom care manager. In this post hoc analysis, we examined the effects of the intervention on change in symptom scores among YAs and time to improvement to a mild/moderate level in those with at least one severe symptom. Results: Among 40,659 patients who responded to at least one survey, 2,598 were YAs and 38,061 were adults ≥ 40 years. Among YAs, 10.7%, 24.3%, and 65.1% were 18-24 years, 25-31 years, and 32-39 years, respectively. A greater proportion of YA patients were female (61.5% vs 57.0%), of a non-white race (12.4% vs 5.3%), living in an urban setting (65.7% vs 55.1%), single (36.4% vs 9.6%), on non-government insurance (78.1% vs 36.6%), employed (72.6% vs 37.4%), and had a Bachelor’s degree or greater (37.8% vs 28.3%, p < 0.001 for all). Fewer YA patients had metastatic disease compared to older patients (24.2% vs 35.2%, p < 0.001). Compared to a pre-intervention baseline, the mean change in symptom score for YA patients following the intervention demonstrated improvements in anxiety (-0.195) and depression (-0.168, p < 0.0001 for both), while physical function impairment worsened over the intervention period (0.101, p = 0.014). Compared to adults ≥ 40 years, YAs experienced greater intervention effects for management of depression ( p < 0.001), fatigue ( p = 0.01), pain ( p < 0.0001), and physical function impairment ( p < 0.0001). Among YAs with a severe symptom during the intervention period, median time to improvement to a mild/moderate level was longer for anxiety compared to those ≥ 40 years (3.5 vs 2.7 months, p = 0.009). Conclusions: Routine ePROM surveillance, coupled with CC-based symptom management, led to improvements in anxiety and depression among YAs with cancer, although, time to improvement was longer for anxiety compared to adults ≥ 40 years.

11177 Background: Early detection of recurrence after curative-intent treatment is a critical priority, traditional imaging often detects relapse when disease burden is high, potentially limiting treatment efficacy. ctDNA has emerged as an established prognostic biomarker for molecular residual disease (MRD) detection and early relapse. We performed a real-world meta-analysis on published datasets that utilized personalized, tumor-informed ctDNA testing to assess its performance across tumor types and clinical management approaches. Methods: Real-world studies published from December 2022 to December 2025 using the personalized, tumor-informed Signatera ctDNA assay (Natera, Inc.) were included. Eligibility required ctDNA assessment in the MRD (2–16 weeks post-surgery (histology dependent)/pre adjuvant therapy (ACT)) and/or surveillance (post-ACT/end of the MRD window if no ACT was given) settings, with outcomes stratified by ctDNA status and hazard ratios (HR) reported from univariable or time-dependent Cox regression analysis. Exclusions included: clinical trials, biobanks, metastatic disease treated with palliative intent, case reports, reviews, editorials, or commentaries. Clinical outcomes were harmonized into a composite event-free survival (EFS) endpoint (time to recurrence, progression, or death). Pooled HRs and 95% CIs were estimated using random and fixed effects models and heterogeneity between studies was assessed using the I 2 and Cochran’s Q test. Median lead time from ctDNA-positivity to radiographic or clinical recurrence was summarized when available. Results: We identified 18 eligible publications comprising 3,004 unique patients across 15 solid tumor types. During the MRD window, ctDNA positivity was associated with a significantly increased risk of an EFS event compared with ctDNA negativity (pooled HR: 8.15; 95% CI: 6.12–10.85, I 2 = 0.00%, P = 0.844, n = 13). During the surveillance window, inclusive of post-definitive treatment, ctDNA positivity conferred an even greater EFS risk (pooled HR: 18.30; 95% CI: 14.17–23.65, I 2 = 0%, P = 0.911 for heterogeneity, n = 16). Across studies, ctDNA detection during surveillance preceded radiographic or clinical recurrence by a median of 3.20 months (95% CI: 2.50-4.10, P < 0.0001, n = 10), although this varied substantially by study/tumor type (I 2 = 80.9%). Conclusions: In this pan-cancer real-world meta-analysis, ctDNA positivity assessed using a tumor-informed assay was highly prognostic following curative-intent therapy at all timepoints evaluated with low heterogeneity between studies. These findings support the broad clinical utility of tumor-informed ctDNA testing for post-treatment risk stratification and longitudinal disease monitoring across solid tumors.

SUMMARY Neurodegenerative diseases are often accompanied by systemic comorbidities, including changes in bone health, but the molecular relationship between neurodegeneration, skeletal decline, and cellular senescence remains poorly understood. In this study, we investigated sex-specific changes in circulating bone- and senescence-related proteins across the spectrum of Alzheimer’s disease(AD), Lewbody dementia(LB) and Parkinson’s disease(PD). Plasma proteomic profiling was performed on samples from 408 participants deeply phenotyped for neurodegenerative diseases, followed by differential protein and pathway analyses. This study reveals sex-dependent alterations in bone and senescence-related circulating proteins in AD-related, PD and LB-related neurodegenerative diseases, providing insights into the complex relationship between neurodegeneration and bone health. Several candidate proteins were also associated with established plasma neurodegeneration biomarkers, particularly pTau181. Pathway analyses revealed shared mitochondrial and metabolic dysfunction across neurodegenerative diseases, with disease-specific features including vesicle trafficking disruption in AD and inflammatory-senescence pathways in LB, plus sex-divergent patterns in inflammatory signaling and bone-related pathways.

10030 Background: CABO is a multi-targeted kinase inhibitor of VEGFR2, c-MET, AXL and RET and has shown clinical evidence of activity in two prior studies of adult and pediatric patients with advanced OS. We report results of a feasibility cohort of CABO + MAP chemotherapy in patients with newly diagnosed high-risk OS. Methods: Patients <40 years, body surface area ≥ 0.8 m 2 and new diagnosis of high-grade OS with metastatic disease and resectable primary tumor were eligible. Patients were enrolled to two CABO dose levels (Dose Level 1 (DL1) 25 mg/m 2 /day, maximum 40 mg/day; Dose Level 2 (DL2) 35 mg/m 2 /day; maximum 60 mg/day) using a modified IQ 3+3 design. CABO was orally administered concomitantly with six 35-day cycles of MAP (cisplatin 60 mg/m 2 on days 1-2 (cycles 1-4), doxorubicin 37.5 mg/m 2 on days 1-2 (with dexrazoxane), methotrexate 12 g/m 2 on days 22, 29) and for 24 weeks as maintenance monotherapy. CABO was held after 7 weeks and resumed during 4 th MAP cycle to allow for primary tumor resection and metastatic surgeries. Dose-limiting toxicities (DLT) were assessed during weeks 1-6 of treatment; additional monitoring for post-surgical complications was conducted through completion of 4 th MAP cycle. The primary endpoint for this cohort was feasibility of combination therapy. Results: Ten patients (median age 11.5 years, 70% male) were enrolled and treated with CABO + MAP (DL1, n=4; DL2, n=6). Median cumulative doses of all MAP agents were maintained throughout treatment with no dose reductions. Concomitant dosing of CABO with MAP was tolerated with no protocol-specified DLTs occurring during the evaluation period. DL2 (35 mg/m 2 ) was established as the recommended dose for further study of combination therapy. Commonly reported adverse events included hematologic toxicities, febrile neutropenia, and alanine/aspartate aminotransferase (AST/ALT) elevation. Interruption of CABO was required in 6 patients for Grade 3+ AST/ALT elevation following methotrexate (n=3), wound complications (n=3), and Grade 3 pneumothorax (n=1). Wounds included two Grade 3 port site events and one Grade 1 primary tumor resection site; two patients later resumed CABO after healing without wound recurrence. Dose reduction of CABO was required in one patient for Grade 4 amylase elevation. Conclusions: The combination of CABO + MAP is feasible with no protocol-specified DLTs during the evaluation period. Generalizability is limited based on cohort size. Further evaluation of CABO + MAP is ongoing in a phase II/III randomized efficacy study in newly diagnosed standard and high-risk patients using CABO dose of 35 mg/m 2 /day (max 60 mg), with delayed initiation of CABO in patients with port placement and early safety monitoring for wound-related events, as well as full study monitoring of dose delivery, wound complications and systemic toxicity. Clinical trial information: NCT05691478 .

Estimates of fibromyalgia prevalence vary widely worldwide due to differences in diagnostic criteria, study methodology, and population characteristics. Accurate estimates are essential to inform population-level surveillance, guide resource allocation, and highlight disparities in disease recognition and access to care. The objective of this systematic review and meta-analysis was to determine the global prevalence of fibromyalgia in the general population, and secondarily to identify factors moderating prevalence variation and to assess prevalence in defined at-risk subpopulations. Pooled prevalence estimates with 95% confidence intervals (CIs) were calculated using the inverse variance heterogeneity model with Freeman–Tukey transformation. Subgroup analyses were performed by sex, diagnostic criteria, country, and other study characteristics, and meta-regression assessed moderators including publication year and Human Development Index (HDI). Of 21,645 records identified, 1,728 underwent full-text review and 882 studies were included in the final analysis. Across 38 countries and 30,070,032 individuals (188 studies), the pooled fibromyalgia prevalence in the general population was 1.40% (95% CI, 0.49–2.47), with substantial heterogeneity (I 2 = 100%) and very low certainty of evidence. Among at-risk subpopulations (9,771,123 participants; 768 studies), prevalence was markedly higher in autoimmune and inflammatory conditions, such as chronic urticaria (37.1%), interstitial cystitis (30.8%), systemic sclerosis (20.6%), celiac disease (20.5%), and inflammatory bowel disease (19.9%), and elevated in chronic pain, rheumatologic, and post-infection cohorts. Meta-regression identified publication year (β = 0.008, P < .001) and HDI (β = 0.725, P = .002) as significant moderators of prevalence. In conclusion, fibromyalgia affects 1% to 2% of the global population, with substantially higher rates in at-risk subpopulations. Temporal and socioeconomic trends emphasize diagnostic inconsistency and global disparities in care.

Importance Ischemia-reperfusion injury contributes to graft dysfunction after liver transplant. Hypothermic oxygenated perfusion (HOPE) has been shown to improve liver function, but its benefit in extended criteria donors in a US population remains unclear. Objective To assess whether back-to-base portal-venous HOPE impacts outcomes after liver transplant in the US. Design, Setting, and Participants The Bridge to HOPE Trial is a multicenter, randomized, open-label trial with 1-year follow-up. The study took place at 15 US liver transplant centers and patients were enrolled between January 2021 and May 2023. Central assessment of complications and cholangiograms for nonanastomotic biliary strictures (NAS) was blinded to treatment arm. Participants included 219 recipients of extended-criteria donor livers after brain death (DBD) and after circulatory death (DCD) who were randomized 1:1 to HOPE after static cold storage (SCS) (n = 109) or SCS only (n = 110). Randomization was performed after liver inspection and acceptance for transplant. Data were analyzed from December 2024 to July 2025. Intervention After SCS and transport, livers underwent portal-venous HOPE until implant, using the VitaSmart HOPE System. Main Outcomes and Measures The primary efficacy end point was early allograft dysfunction (EAD). Other main outcomes included model for early allograft function (MEAF) score, hospital length of stay (LOS), patient and graft survival, and biliary complications. Additional post hoc analyses were performed. Results Overall, 219 patients (82 female [37.4%] and 137 male[62.6%]) were included (DCD, 57 of 219 [26%]) with 97% (212 of 219) completing 12-month follow-up. EAD incidence was 20.2% (22 of 109) with HOPE vs 37.3% (41 of 110) with SCS (rate difference, −17.1%; 95% CI, −27.2 to −7.0; noninferiority P &amp;lt; .001; superiority P = .005). HOPE treatment led to significantly lower MEAF mean (SD) scores (HOPE group, 4.28 [1.75]; control group, 4.82 [1.85]; mean difference, −0.54; 95% CI, −1.02 to −0.06; P = .03) and shorter median LOS (hazard ratio, 1.32; 95% CI, 1.01-1.73; P = .04). NAS on imaging and 1-year survivals were comparable between groups (patients: HOPE group, 106 of 109 [97.2%] vs SCS, 106 of 110 [96.4%]; graft: HOPE group, 104 of 109 [95.4%] vs SCS, 102 of 110 [92.7%]). Post hoc analyses showed numerically less graft loss due to NAS after HOPE (4 vs 1) and less major complications (Clavien-Dindo classification ≥IIIa) per patient, respectively. Conclusions and Relevance Back-to-base portal-venous HOPE was compared with SCS alone for extended risk DBD and DCD livers. The HOPE approach was safe and associated with reduced EAD, MEAF score, and LOS. These findings support the use of HOPE as a pragmatic strategy to improve early posttransplant outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT05045794 .